The Oklahoma Medical Research Foundation is home to outstanding clinical and basic science investigators who have research interests in the etiology and pathogenesis of autoimmune diseases and seek to identify novel therapeutics for more effective patient treatments. The scientific expertise, extensive clinical trial experience, access to geographically distinct patient populations, as well as unique patient registries, repositories and core technologies provide a solid foundation for the Oklahoma Autoimmunity Center of Excellence (ACE) application to which we have added a multidisciplinary team of clinical and basic science investigators. The focus of the Oklahoma ACE application is on expediting the translation of scientific discoveries in autoimmunity to clinical application in the diagnosis and treatment of systemic autoimmune diseases. To accomplish this, the Oklahoma ACE comprises two research projects, a proposed pilot research project, a Clinical Center (Joan Merrill, PI) and an administrative core (Judith James, PI). The research projects focus on thrombotic thrombocytopenic purpura, systemic lupus erythematosus, and Sj"gren's syndrome, which are also focuses of the Clinical Center. Multiple sclerosis, rheumatoid arthritis, pediatric arthritis, insulin-dependent diabetes, idiopathic thrombocytopenia and pediatric lupus are other key disease emphases of the Clinical Center. Two complimentary, but unique, research projects focus on understanding early events in the development of lupus autoimmunity and in defining targetable genetic associations in Sj"gren's syndrome. The pilot project uses complimentary methods to address roles of elevated interferon activity in patients with TTP and a novel animal model of thrombocytopenia. In addition, two clinical trials are proposed;both of which enhance or build upon the basic science projects. The first studies efficacy and mechanistic affects of anti-IFN in select SLE patient subsets by applying a patient centric, dose optimization strategy. The second tests the efficacy and early MRI changes of a novel MEK1/MEK2 inhibitor in RA with additional mechanistic studies. The Administrative Core will provide leadership and management through acting on behalf of the Oklahoma ACE members within the ACE Network and NIH Program, ensuring fiscal responsibility for the ACE, and providing an educational foundation for a multi-disciplinary approach to autoimmune disease research. Thus, the Oklahoma ACE will unite Oklahoma-based clinical and basic science experts to facilitate access to unique patient populations for participation in clinical trials and to understand basic mechanisms of etiology and pathogenesis. The Oklahoma ACE brings together adult and pediatric rheumatologists, neurologists, endocrinologists, dermatologists, hematologists, dentists, ophthalmologists, geneticists, immunologists, molecular biologists, epidemiologists and biostatisticians to provide a multidisciplinary approach to discovering and applying novel therapeutics in systemic autoimmune diseases. Through strong basic science projects paired with clinical expertise the Oklahoma ACE will provide unique research and clinical opportunities to the ACE Network. CLINICAL COMPONENT: CLINICAL CENTER (Merrill, J) CLINICAL COMPONENT DESCRIPTION (provided by applicant): The Oklahoma ACE Clinical Center brings together disease-specific and interdisciplinary clinics in systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sj"gren's syndrome, thrombotic thrombocytopenic purpura, insulin dependent diabetes mellitus, pediatric SLE and juvenile inflammatory arthritis to forward translational research in autoimmunity. Patients from each of these disease populations are available and committed to participate in potential national ACE investigations. With adult and pediatric rheumatologists, adult and pediatric endocrinologists, neurologists, hematologists, dermatologists, ophthalmologists and dentists, as well as basic scientists from various areas of immunology, molecular biology, genetics, epidemiology and biostatistics, our investigative team is poised to make basic advances regarding disease pathogenesis and to help translate these discoveries to the clinic. The Clinical Pharmacology program at OMRF will serve as the primary home for the SLE, RA, Sj"gren's syndrome and TTP clinics. Currently leading or participating in more than 20 active clinical trials, this clinical center is accustomed to participating in clinical trials, managing confidential patient information, and providing multidisciplinary care. In addition, the Clinical Pharmacology space provides investigators access to state-of-the-art research tools directly adjacent to the patient care unit. Pediatric IDDM and rheumatology clinics are housed across the street at OUHSC and a large, community based multiple sclerosis clinic will participate for MS patient investigation. Joan Merrill, MD serves as the leader of our Clinical Center. She is the current medical director of the Lupus Foundation of America and a leader in SLE clinical trial development. She has served as the lead investigator on large, multi-site trials. Combining her extensive knowledge of clinical trial design and the known heterogenic presentation of SLE, she proposes to devise patient-centric clinical trials that use biomarkers of disease to optimize therapeutic doses. Our Clinical Center proposes two potential clinical concepts. Based upon our basic science investigation regarding pivotal roles for increased interferon activity in pre-clinical SLE, Sj"gren's syndrome and potentially TTP, our first trial examines the efficacy and biologic impact of anti-INF alpha in SLE patients with arthritis and select dermatologic manifestations. The second trial proposes use of a first-in-class target of MEK1/MEK2 inhibition in RA to assess impact on MRI progression of disease and on select biomarkers. Both of these trials have mechanistic studies proposed to address key scientific questions regarding pathogenesis and response. The Oklahoma Autoimmunity Center of Excellence Clinical Center will provide interdisciplinary investigators with unique populations of well-characterized patients to participate in ACE network autoimmune disease clinical trials. With our rich Native American heritage and large rural populations, the patients provided by the Oklahoma ACE will be previously understudied and provide unique insights for therapeutic trials.